Cargando…

Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy

Pancreatic ductal adenocarcinoma (PDAC) cells utilize a novel non-canonical pathway of glutamine metabolism that is essential for tumor growth and redox balance. Inhibition of this metabolic pathway in PDAC can potentially synergize with therapies that increase intracellular reactive oxygen species...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Doudou, Fu, Zhiqiang, Chen, Ruiwan, Zhao, Xiaohui, Zhou, Yu, Zeng, Bing, Yu, Min, Zhou, Quanbo, Lin, Qing, Gao, Wenchao, Ye, Huilin, Zhou, Jiajia, Li, Zhihua, Liu, Yimin, Chen, Rufu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741594/
https://www.ncbi.nlm.nih.gov/pubmed/26439804
_version_ 1782414026299408384
author Li, Doudou
Fu, Zhiqiang
Chen, Ruiwan
Zhao, Xiaohui
Zhou, Yu
Zeng, Bing
Yu, Min
Zhou, Quanbo
Lin, Qing
Gao, Wenchao
Ye, Huilin
Zhou, Jiajia
Li, Zhihua
Liu, Yimin
Chen, Rufu
author_facet Li, Doudou
Fu, Zhiqiang
Chen, Ruiwan
Zhao, Xiaohui
Zhou, Yu
Zeng, Bing
Yu, Min
Zhou, Quanbo
Lin, Qing
Gao, Wenchao
Ye, Huilin
Zhou, Jiajia
Li, Zhihua
Liu, Yimin
Chen, Rufu
author_sort Li, Doudou
collection PubMed
description Pancreatic ductal adenocarcinoma (PDAC) cells utilize a novel non-canonical pathway of glutamine metabolism that is essential for tumor growth and redox balance. Inhibition of this metabolic pathway in PDAC can potentially synergize with therapies that increase intracellular reactive oxygen species (ROS) such as radiation. Here, we evaluated the dependence of pancreatic cancer stem cells (PCSCs) on this non-canonical glutamine metabolism pathway and researched whether inhibiting this pathway can enhance radiosensitivity of PCSCs. We showed that glutamine deprivation significantly inhibited self-renewal, decreased expression of stemness-related genes, increased intracellular ROS, and induced apoptosis in PCSCs. These effects were countered by oxaloacetate, but not α-ketoglutarate. Knockdown of glutamic-oxaloacetic transaminase dramatically impaired PCSCs properties, while glutamate dehydrogenase knockdown had a limited effect, suggesting a dependence of PCSCs on non-canonical glutamine metabolism. Additionally, glutamine deprivation significantly increased radiation-induced ROS and sensitized PCSCs to fractionated radiation. Moreover, transaminase inhibitors effectively enhanced ROS generation, promoted radiation sensitivity, and attenuated tumor growth in nude mice following radiation exposure. Our findings reveal that inhibiting the non-canonical pathway of glutamine metabolism enhances the PCSC radiosensitivity and may be an effective adjunct in cancer radiotherapy.
format Online
Article
Text
id pubmed-4741594
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-47415942016-03-03 Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy Li, Doudou Fu, Zhiqiang Chen, Ruiwan Zhao, Xiaohui Zhou, Yu Zeng, Bing Yu, Min Zhou, Quanbo Lin, Qing Gao, Wenchao Ye, Huilin Zhou, Jiajia Li, Zhihua Liu, Yimin Chen, Rufu Oncotarget Research Paper Pancreatic ductal adenocarcinoma (PDAC) cells utilize a novel non-canonical pathway of glutamine metabolism that is essential for tumor growth and redox balance. Inhibition of this metabolic pathway in PDAC can potentially synergize with therapies that increase intracellular reactive oxygen species (ROS) such as radiation. Here, we evaluated the dependence of pancreatic cancer stem cells (PCSCs) on this non-canonical glutamine metabolism pathway and researched whether inhibiting this pathway can enhance radiosensitivity of PCSCs. We showed that glutamine deprivation significantly inhibited self-renewal, decreased expression of stemness-related genes, increased intracellular ROS, and induced apoptosis in PCSCs. These effects were countered by oxaloacetate, but not α-ketoglutarate. Knockdown of glutamic-oxaloacetic transaminase dramatically impaired PCSCs properties, while glutamate dehydrogenase knockdown had a limited effect, suggesting a dependence of PCSCs on non-canonical glutamine metabolism. Additionally, glutamine deprivation significantly increased radiation-induced ROS and sensitized PCSCs to fractionated radiation. Moreover, transaminase inhibitors effectively enhanced ROS generation, promoted radiation sensitivity, and attenuated tumor growth in nude mice following radiation exposure. Our findings reveal that inhibiting the non-canonical pathway of glutamine metabolism enhances the PCSC radiosensitivity and may be an effective adjunct in cancer radiotherapy. Impact Journals LLC 2015-09-03 /pmc/articles/PMC4741594/ /pubmed/26439804 Text en Copyright: © 2015 Li et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Li, Doudou
Fu, Zhiqiang
Chen, Ruiwan
Zhao, Xiaohui
Zhou, Yu
Zeng, Bing
Yu, Min
Zhou, Quanbo
Lin, Qing
Gao, Wenchao
Ye, Huilin
Zhou, Jiajia
Li, Zhihua
Liu, Yimin
Chen, Rufu
Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy
title Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy
title_full Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy
title_fullStr Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy
title_full_unstemmed Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy
title_short Inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy
title_sort inhibition of glutamine metabolism counteracts pancreatic cancer stem cell features and sensitizes cells to radiotherapy
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741594/
https://www.ncbi.nlm.nih.gov/pubmed/26439804
work_keys_str_mv AT lidoudou inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT fuzhiqiang inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT chenruiwan inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT zhaoxiaohui inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT zhouyu inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT zengbing inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT yumin inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT zhouquanbo inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT linqing inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT gaowenchao inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT yehuilin inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT zhoujiajia inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT lizhihua inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT liuyimin inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy
AT chenrufu inhibitionofglutaminemetabolismcounteractspancreaticcancerstemcellfeaturesandsensitizescellstoradiotherapy